Increased rates of infertility accompanied by the delay in age at marriage and declining birthrates have been global problems in advanced countries of the day. It is likely that interest in sterility treatment will continue to grow more and more in the future.
Treatment of sterility due to disorders of ovulation in women involves stimulation of follicular development by recombinant FSH (follicle stimulating hormone) or human menopausal gonadotropins (hMG preparations), induction of ovulation by human chorionic gonadotropins (hCG), and the like. Artificial insemination has also frequently been used, and superovulation treatment through hMG-hCG therapy has been applied widely. In the normal menstrual cycle, luteinizing hormone (LH) surged up from the pituitary is received on LH receptors in mature follicular granulosa cells, whereby ovulation is induced. The hCG described above is based on the mimicry of this endogenous LH surge, and stimulation of LH receptors by hCG in lieu of LH is the mechanism of inducing ovulation. In addition, production techniques for recombinant human LH (rhLH) was developed recently, and ovulation induction treatment with rhLH has also started (J. Clin. Endocrinol. Metab., 86, 2607-2618, 2001). In the ovary which receives LH, the expression of many genes is induced, which subsequently leads to ovulation. What is directly involved in ovulation phenomenon is a gene product induced by LH, rather than LH itself. It is reported that when downstream genes for LH such as progesterone receptor or cyclooxygenase-2 are knocked out, ovulation is inhibited (reviews: Steroids, 65, 559-570, 2000; Endocrinology, 143, 2823-2835, 2002). With expanding hMG-hCG therapy, patients with developed complications increased, which has become a clinically serious problem. One of the highest incidences of complications is ovarian hyperstimulation syndrome (OHSS). OHSS is an iatrogenic disorder and is onset by administration of hMG or hCG or overproduction of hCG in mother body after conception. In its severe form, ovarian enlargement and ascites occur, and may be even life-threatening for patients. For this reason, there are a variety of diagnostic techniques for preventing OHSS in the clinical phase. When blood estrogen shows a high level, or when polycystic ovaries are observed by ultrasound scanning, measures to discontinue ovulation induction, etc. are taken (Acta Obstet. Gynecol. Scand. 80, 878-882, 2001).
For sterility having causes relating to the man, medical or surgical treatment is available when physical factors such as varicoceles or seminal tract obstruction, etc. are found. However, when its causes are found in reproductive functions such as disorder of sperm producing function, ejaculatory dysfunction, etc., any effective treatment has hardly been established.
Gonadotropins (gonad-stimulating hormone) such as FSH, LH, etc., which are released from the pituitary are largely involved in maturation of ova or sperm and stimulate the secretion of estrogen and progesterone from the ovaries. Release of these gonadotropins is induced by GnRH (gonadotropin-releasing hormone) secreted from the hypothalamus. Normally, GnRH is released intermittently so that FSH and LH are released at certain intervals. Pulsatile release of GnRH is crucial for maintenance of gonadotropins in blood to a certain level and continuous administration of GnRH conversely results in decreased level of gonadotropins in blood (Science, 202, 631-633, 1978). FSH and LH released pulsatile stimulate maturation of the ovum and sperm in the ovary and testicle, respectively, synthesis of sex hormones, and the like. The pulsatile release of GnRH and gonadotropins also takes part in development of reproductive organs in childhood and maturation of the reproductive organs during adolescence. In addition, ovulation is induced by an LH and FSH surge immediately before ovulation, and reportedly GnRH is surged strongly also in this occasion. As such, GnRH and gonadotropins are important factors for supporting reproductive functions in both female and male individuals and abnormalities in these functions are reflected as reproductive abnormalities involving infertility mainly (Endocrinology, 143, 2823-2835, 2002).
On the other hand, human metastin (human KiSS-1 peptide) is a peptide consisting of 54 amino acids, purified from human placenta and was found to be the ligand for a G-protein-coupled human OT7T175 (WO 00/24890). Rat type (rat metastin) and mouse type (mouse metastin) of human metastin are also reported (WO 01/75104). Metastin has a cancer metastasis inhibiting activity and is useful for the prevention/treatment of cancers (e.g., lung cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, rectal cancer, colon cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer, kidney cancer, bladder cancer, brain tumor, etc.); metastin has a pancreatic function regulating action and is useful for the prevention/treatment of pancreatic diseases (e.g., acute or chronic pancreatitis, pancreatic cancer, etc.), and metastin has a placenta function regulating action and is useful for the prevention/treatment of choriocarcinoma, hydatid moles, invasive moles, miscarriage, fetal hypoplasia, sugar dysbolism, lipid dysbolism or abnormal delivery (WO 00/24890, WO 01/75104, etc.). Furthermore, sustained preparations containing metastin are reported (WO 02/85399). Recently, it is reported that the metastin level in blood from pregnant women rapidly rises with initiation of pregnancy and its expression is maintained at a high level until delivery (J. Clin. Endocrinol Metab., 88, 914-919, 2003).
Since the actual mechanism for the onset of OHSS remains elusive, women with severe infertility should be given hMG-hCG therapy, etc., OHSS is considered an unavoidable disease in the current fertility treatment. It has been desired to develop ovulation inducers having an ovulation-promoting effect comparable to conventional ovulation inducers represented by hCG without causing OHSS. It has also been desired to develop drugs effective for male infertility.